Genital herpes infection is extremely common throughout the world and continues to increase in incidence, Genital herpes is caused by the sexual transmission of herpes simplex virus type 2 (HSV-2), although a smaller, but increasing, percentage of cases are caused by herpes simplex virus type 1 (HSV-1) Genital herpes infection is associated with a range of clinical sequlae, including many that are serious in nature. The lack of effective measures to impede HSV transmission underlies the widespread escalation of the genital herpes epidemic. We are developing a novel approach to block HSV transmission in women. This approach, termed MucoCept HSV, involves genetic modification of human vaginal isolates of lactobacilli, the common bacterium found within the vaginal mucosal microflora of healthy women. These bacteria are being modified to produce a decoy HSV receptor that has the capacity to bind, trap, and inactivate HSV within the mucosal layer before it is transmitted to host cell and tissues. As such, this represents a novel and potentially powerful approach to prevent the transmission of HSV. As outlined in the present application, we propose to genetically modify vaginal-derived lactobacilli to express the HSV receptor, HveC, either covalently attached to the cell wall of the bacterium, or secreted into the surrounding biofilm matrix. This approach will use technology that has already been used by our group for the successful expression of other heterologous mammalian proteins in these same strains of lactobacilli. We propose to subsequently demonstrate the capacity of the expressed HveC protein to neutralize HSV infectivity of susceptible cultured cell lines. If achieved successfully, these studies will position us to undertake Phase II studies to assess the efficacy of these modified bacteria to reduce HSV transmission in vivo, as well as to optimize stable expression of the HveC protein as a major component of the clinical development plan for this product.